Mechanical and thermal hyperalgesia in patients with poliomyelitis

Mechanical and thermal hyperalgesia in patients with poliomyelitis

Clinical Neurophysiology 124 (2013) 1431–1438 Contents lists available at SciVerse ScienceDirect Clinical Neurophysiology journal homepage: www.else...

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Clinical Neurophysiology 124 (2013) 1431–1438

Contents lists available at SciVerse ScienceDirect

Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph

Mechanical and thermal hyperalgesia in patients with poliomyelitis Hatice Kumru a,b,⇑,1, Enric Portell a,b,1, Marti Marti a,b, Sergiu Albu a,b, Josep M Tormos a,b, Joan Vidal a,b, Josep Valls-Sole c a

Institut Guttmann, Institut Universitari de Neurorehabilitació Adscrit a la UAB, 08916 Badalona, Barcelona, Spain Univ. Autonoma de Barcelona, 08193 Bellaterra, Cerdanyola del Vallès, Spain c Hospital Clinic, Institut d’Investigació Biomèdica August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain b

a r t i c l e

i n f o

Article history: Accepted 1 January 2013 Available online 13 February 2013 Keywords: Mechanical pain Heat pain Evoked pain Hyperalgesia Poliomyelitis

h i g h l i g h t s  Evoked pain perception and contact heat evoked potentials are abnormal in some patients with paralytic poliomyelitis.  Alteration in the processing of somatosensory inputs in pPM may contribute to further understanding the mechanisms underlying pain in clinical practice.  Hyperalgesia should be taken into account in the routine clinical evaluation and management of patients with pPM.

a b s t r a c t Objective: Paralytic poliomyelitis (pPM) is clinically suspected in individuals experiencing a non-progressive syndrome of flaccid paralysis and atrophy as a sequel of an acute infection. Despite normal sensory perception, patients with pPM complain of pain more than matched siblings. Here, we studied the characteristics of evoked pain in a cohort of pPM patients using contact heat evoked potentials and psychophysical tests. Methods: Fifteen patients with pPM and 15 controls were studied. Inclusion criteria were unilateral or asymmetric involvement of lower extremities. Mechanical, warm and heat pain perception thresholds and evoked pain were measured in both thighs. Contact heat evoked potentials were recorded from the vertex. Results: Mechanical and heat pain thresholds were significantly lower in the affected than in the lessaffected leg or in the legs of controls. Evoked pain ratings were significantly higher in the affected leg than in either the less-affected leg or in controls. Evoked potentials were significantly higher in the affected than in the less-affected leg. Conclusion: Patients with pPM have mechanical and thermal hyperalgesia, which suggests abnormalities in processing of somatosensory inputs in these patients. Significance: This phenomenon should be taken into account in the routine clinical evaluation and management of pPM patients. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Poliovirus spreads along nerve pathways, preferentially replicating in, and destroying, motor neurons within the spinal cord, brain stem and motor cortex (Nagata et al., 2004; Sabin, 1942; Swan, 1939). Neurological damage results mainly from destruction of lower motor neurons in the anterior horns (Sabin, 1942; Swan, ⇑ Corresponding author. Address: Hospital de Neurorehabilitació Institut Guttmann, Camí Can Ruti s/n. Barcelona, 08916 Barcelona, Spain. Tel.: +34 93 4977700; fax: +34 93 4977715. E-mail address: [email protected] (H. Kumru). 1 These authors equally participated in this study.

1939; Erb, 1931). This induces a flaccid paralysis that usually leads to a clinically evident sequel of non-progressive motor deficit in one or more limbs with decreased or absent tendon reflexes and without sensory or cognitive loss (MMWR Recomm Rep., 1997). Despite normal sensory perception, patients with paralytic poliomyelitis (pPM) complain of tiredness and pain significantly more than matched siblings (Hildegunn et al., 2007; Farbu and Gilhus, 2002). Previous studies revealed that up to 60% of pPM patients reported pain as a disabling health problem (Rekand et al., 2009, 2000; Hildegunn et al., 2007; Farbu et al., 2003; Farbu and Gilhus, 2002; Willen and Grimby, 1998). The activities of daily living and the quality of life may be influenced by the pain (Hildegunn et al., 2007; Farbu and Gilhus, 2002; Rekand et al., 2000). A

1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.01.009

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number of studies consider pain in those patients as highly dependent on psycho-social factors (Hirsh et al., 2010) but no systematic study has assessed so far the characteristics of pain in pPM patients. We hypothesized that pain in pPM patients might arise from a genuine somatosensory dysfunction, either related to the disease itself or to the development of maladaptive mechanisms. If this is the case, we can expect to find signs of impairment in the nociceptive pathway that would be more marked in the lower limb with more prominent clinical impairment (affected leg) than in the contralateral one (non- or less-affected leg). Therefore, we studied the characteristics of evoked pain in pPM patients using psychophysical testing and contact heat evoked potentials (CHEPs). 2. Patients and methods Fifteen patients were selected among those with pPM being followed in our centre. They were consecutively included in the study if they fulfilled the following inclusion criteria: (1) unilateral or asymmetric involvement of the lower limbs, (2) absence of any neurological impairment that could be attributed to causes other than pPM, (3) absence of moderate or severe depression. The control group was composed of age and gender matched healthy controls (n = 15) with no symptoms or signs of any neurological disease. The Institutional review board and the Ethical Committee of Institut Guttmann revised and approved the protocol. All subjects gave written informed consent for the study.

intensity and localization. The types of pain were classified according to the IASP Task Force on pain from spinal injury (Siddall et al., 2000) after the neurological examination and after interviewing the patient about pain characteristics. Pain was classified as nociceptive when aching in an area with signs of inflammation and painful joint movements (Werhagen and Borg, 2010; Siddall et al., 2000). Musculoskeletal pain is one form of nociceptive pain which is dull, aching, movement-related, eased by rest, responsive to opioids and NSAIDs, which is located in musculoskeletal structures (Siddall et al., 2000). Pain was classified as neuropathic when patients described burning or shooting sensations in an area with sensory disturbances to pinprick and touch and without relation to movements or signs of inflammation (Werhagen and Borg, 2010; Siddall et al., 2000). The numerical ratings scale (NRS) ranging from 0 to 10, with the definition of 0 meaning ‘No pain’ and 10 meaning ‘Worst imaginable pain’ was used to quantify pain intensity. 3.2. Conventional nerve conduction study and somatosensory evoked potentials in PM To document if there was sensory impairment in lower limbs, sensory nerve conduction tests were performed according to conventional techniques in sural and superficial peroneal nerves from both sides with measurement of conduction velocity and amplitude of the action potentials. For somatosensory evoked potentials (SEPs) the posterior tibial nerves were stimulated at the medial malleolus. Recordings were done at Cz with the reference to Fz.

3. Experimental procedure

3.3. Mechanical pain perception threshold

All patients and healthy controls underwent the following tests: (1) clinical evaluation, (2) psychophysical study (mechanical, warm and heat pain perception threshold), (3) contact heat evoked potentials (CHEPs) and evoked heat pain perception.

Mechanical pain perception threshold was measured using a blood pressure cuff (Speidel and Keller, Germany) around the thighs. The study was carried out in 13 patients and 12 controls lying in supine position. The cuff pressure was raised at a rate of 5 mmHg every 2 s. Subjects were instructed to indicate whether pain was felt after each level of inflation. Mechanical pain threshold was determined as the mean cuff pressure value obtained after repeating 4 times the procedure with breaks of at least 30 s between subsequent trials.

3.1. Clinical features of patients All patients underwent an interview to assess the clinical and demographic characteristics of pPM, including specific questions regarding pain (Table 1). We carried out a neurological examination, including a thorough assessment of sensory functions, using conventional clinical methods. We then carried out a psychophysical thermal testing The present study analyzed longstanding and ongoing pain, where ‘‘longstanding’’ indicated duration of at least 3 months. Patients reporting pain were asked to describe precisely its character,

3.4. Warm and heat pain perception threshold Thermal threshold to warm sensation and heat pain were measured with a Medoc Thermal Sensory Analyser (Pathway; MedocÒ, Ramat Yishai, Israel) equipped with a 5.7 cm2 probe, using the method of limits. Subjects were examined in the sitting position

Table 1 Clinical and demographic characteristics of patients with PM and characteristics of ongoing pain. Age (years)

Gender

Time since PM (years)

More affected limb

Type of ongoing pain

Intensity of ongoing pain

Localization of pain

50 58 54 54 62 54 64 50 50 51 56 57 56 48 60

F M F M F M M F F M M M M F F

49 57 52 53 59 53 62 48 49 50 55 56 54 47 58

R R L L R R R R L R L L R R R

Nociceptive – Nociceptive Nociceptive Nociceptive – Nociceptive Nociceptive Nociceptive Nociceptive Nociceptive Nociceptive Nociceptive Nociceptive Nociceptive

4 0 9 4 8 0 2 7 6 3 7 6 2 3 2

Cervical, lumbar, knee – Cervical, lumbar, ankle Knee Cervical, lumbar, pelvis, knees, ankle – Cervical, lumbar, knee Lumbar, knee Lumbar, elbow, knee Shoulder, knee, ankle Cervical, lumbar, ankle Cervical, lumbar, lower limb Lumbar, lower limb Shoulder, lumbar, knee Ankle

The more affected limb refers to the lower limb with more motor involvement due to PM. The intensity of the ongoing pain was measured with an RNS score where 0 means no pain and 10 means the most pain experienced.

H. Kumru et al. / Clinical Neurophysiology 124 (2013) 1431–1438

in a quiet room. Stimuli were applied at three sites: at both thighs and at the left forearm in random order. In 2 patients who had clinically relevant involvement of their right arm, warm and heat pain threshold were measured in both forearms. Subjects were required to stop the progressive stimulus intensity increase by pressing a button as soon as they perceived the specific thermal modality being tested (four stimuli for warm perception threshold and four stimuli for heat pain perception threshold). The stimuli started at an adaptation temperature of 32 °C and increased at a rate of 1 °C/s. Cut-off temperature was 51 °C. Thresholds of warm and heat pain sensations were taken as the average of four successive readings in each subject.

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Spearman’s rank correlation was used for correlation between ongoing pain and evoked pain perception from each thigh. Statistical analyses were performed with the SPSS 13.0 software. A value of p 6 0.05 was considered for statistical significance. 4. Results Clinical and demographic characteristics of patients are given in Table 1. There were no statistically significant differences between groups regarding subjects’ age (p = 0.5) and gender (in controls, male/female: 8/7) (p = 1). Mean age was 54.6 ± 5.1 years for pPM patients, and 53.6 ± 5.1 years for controls. The time since patients had the acute poliomyelitis infection was 53.6 ± 4.4 years (Table 1).

3.5. Contact heat evoked potentials (CHEPs) Thermal stimuli were delivered using Pathway (Medoc, Ramat Yishai, Israel), equipped with a fast heating/fast-cooling probe of 5.7-cm2 surface area. Stimuli were delivered at the fastest available ramp rate of 70 °C/s from a baseline temperature of 32 °C to a maximum of 51°. In each subject, we applied 14–18 heat pulses at each thigh with an interstimulus time interval of 30 s. During the acquisition of CHEPs, subjects were instructed to keep their eyes closed in a fixed, neutral position for at least 2 s after perception of the stimulus to avoid blinking artefacts. For CHEPs recording, we used 9 mm Ag/AgCl surface disc electrodes filled with conductive adhesive gel. The active electrode was placed on Cz, where the pain related-evoked potentials are maximal (Bromm and Treede, 1987). The reference was taken from the contralateral earlobe and the ground electrode was placed on the right arm. The analysis time was 1 s. The amplifier bandpass frequency filter was 0.1–50 Hz. The gain was 50 lV/division. The impedance was kept less than 5 kX. CHEPs were recorded using routine electrodiagnostic equipment (Medelec Synergy, Oxford Instruments, Surrey, England). Data were collected with a sampling rate of 1000 Hz and analysed off-line. 3.6. Evoked heat pain For each patient, we recorded their subjective evoked pain perception using NRS (scale ranged from 0 to 10) following each of the 14 stimuli applied to each thigh used to obtain the CHEPs. 3.7. Data collection and statistical analysis The data in patients were collected from the clinically affected lower limb ‘‘affected leg’’, from the non- or less-affected lower limb ‘‘less-affected leg’’ and from the forearm. For psychophysical tests, we determined the mean threshold values for mechanical pain, warm and heat pain perception threshold for each subject. For CHEPs, we measured latency of relevant peaks (N2 and P2) and peak to peak amplitude of the N2/P2 in the EPs obtained after averaging 14 waveforms for each patient and thigh. Then, we calculated the mean, standard deviation (SD) and standard error of mean (SEM) for all variables in each group of subjects and determined the 95% confidence intervals (CI) in the control group. The Mann Whitney-U and Chi-square tests were used for comparison of demographical and clinical data between patients and controls. We used a 2-way ANOVA with repeated measures on the factor ‘side’ (affected vs. less-affected) and on the factor ‘group’ (patient vs. control). This procedure involved assigning the data obtained in the right and left legs of our controls as respectively, sham-affected and sham-less affected legs, with the exact same proportion of right vs. left sham as right vs. left involvement in patients. Paired or independent t tests were used for post hoc analysis.

4.1. Clinical features of patients Clinical involvement was apparent in the right lower limb in 8 patients and in the left lower limb in 4. In 3 patients, both lower limbs were apparently involved but the physical exam showed a predominant involvement of the right limb in 2 and of the left limb in 1. Two patients with predominantly right lower limb involvement had also clinically relevant right arm involvement. Thirteen patients reported long lasting nociceptive (mainly musculoskeletal) pain predominantly in the less-affected leg with a mean pain intensity of 4.5 ± 2.3 (according to numerical rating scale ‘‘NRS’’). The same patients reported ongoing nociceptive pain during the last 24 h, with a mean intensity of 4.2 ± 2.6 (range: 1–8) (Table 1). Two patients did not report any chronic or acute pain history. None of the patients reported neuropathic pain. During neurological examination, we did not find any sensory deficit to tactile and pinprick stimuli in both lower limbs in pPM patients. Patients reported no differences in sensory perception between both lower limbs at the time of the clinical exam. However, results were different in a second questioning done after finding heat and evoked pain perception differences between lower limbs in the neurophysiological and psychophysical examination. At this time, patients were asked specifically if they noticed differences between legs in pain perception. The responses to this second questioning revealed that (1) all women had more pain in the affected leg than in the less-affected leg during depilation; (2) 6 patients did not allow for treatments requiring injections to be applied to the gluteus in the affected side because of pain; (3) 3 patients reported annoyance during massage in the affected leg; (4) 12 patients reported more pain after minimum trauma or surgical events in the affected leg than in the less-affected leg; (5) 2 patients with arm involvement, did not permit blood extraction from the affected arm because of pain. 4.2. Conventional nerve conduction study and somatosensory evoked potentials Latency and amplitude of SEPs and sural and superficial peroneal nerve conduction velocity and action potential amplitude were similar in affected and less-affected legs in patients (Table 2). 4.3. Mechanical pain perception threshold Data on mechanical pain perception are summarized in Fig. 1 and Table 3. There were significant differences between groups (F = 36.78; p < 0.001) with interaction between side and group (F = 19.60; p < 0.001). The post hoc analysis showed lower mechanical pain perception threshold in the affected-leg than in the lessaffected leg in patients (t = 6.21, p < 0.001), but not between legs of controls (p = 0.7). It was also significantly lower in the affected leg of patients than in the sham-affected leg of controls

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Table 2 Sensory nerve conduction studies and posterior tibial nerve somatosensory evoked potentials (SEPs) in patients with poliomyelitis (PM). Sensory nerve conduction study

SEPs

Sural nerve Velocity (m/s) Affected leg Less-affected leg p

63.7 ± 8.1 62.3 ± 6.9 0.6

Peroneal nerve Amplitude (lV)

Posterior tibial nerve

Velocity (m/s)

22.9 ± 9.4 20.5 ± 11.7 0.6

52.9 ± 4.1 52.8 ± 6.3 0.7

Amplitude (lV)

Latency (ms)

15.0 ± 11.9 20.1 ± 4.4 0.5

P40 41.6 ± 0.9 41.9 ± 0.6 0.5

Amplitude (lV) N45 51.7 ± 2.9 50.2 ± 4.5 0.5

1.7 ± 0.8 1.7 ± 1.0 0.9

Each data show mean ± standard deviation of all pPM patients for affected and less affected legs. ‘‘p’’ value according to paired sample test.

Mechanical pain perception threshold lower extremity p< 0.001

240

p=0.002

Pressure level (mmHg)

210 p<0.001

180

150

120

90

60

30

0

affected

less-affected

1

2

3

sham affected

patients

4

sham less-affected 5

6

controls

Fig. 1. The mechanical pain perception threshold for each studied subject and the average of mechanical pain perception threshold (black vertical line) of the affected leg, and less-affected leg of all patients with pPM and of the legs of controls (sham-affected and sham less-affected). p Value according to paired sample test between the affected and less-affected leg; or according to independent sample test between patients and controls.

Table 3 Psychophysical testing and contact heat evoked potentials (CHEPs) in patients and controls. Patients

Controls

Lower extremity

Mechanical pain (pressure level, mmHg) Warm perception (°C) Heat pain perception (°C) Evoked pain (NRS: 0–10) Amplitude of N2P2 (lV)

Affected

Less-affected

Sham-affected

Sham less-affected

68.4 (6.68) 34.8 (0.19) 38.3 (0.42) 7.1 (0.55) 32.9 (4.25)

107.8 (7.24) 34.4 (0.20) 41.4 (0.44) 5.6 (0.57) 25.7 (3.34)

154 (13.35) 34.3 (0.14) 43.1 (0.39) 3.3 (0.40) 28.3 (4.35)

161.1 (13.59) 34.6 (0.22) 42.6 (0.33) 3.7 (0.33) 26.9 (3.90)

The data reported as a mean (standard error). NRS: numerical rating scale.

(t = 5.82, p < 0.001) and in less affected leg of patients than the sham less-affected leg of controls (t = 3.61, p = 0.002). 4.4. Warm and heat pain perception thresholds 4.4.1. Lower extremity Data on warm and heat pain perception thresholds for leg stimulation are summarized in Fig. 2 and Table 3. There were not significant differences in warm perception threshold (F = 0.40;

p = 0.84), however there was interaction between side and group (F = 4.83; p = 0.037). Differences were not significant for side in patients or controls, neither between the affected side of patients and the sham affected leg of controls, nor between the less affected side of patients and the sham less-affected leg of controls (p > 0.09 for all comparisons). There were also significant differences between groups in heat pain perception threshold (F = 24.70; p < 0.001) with interaction between side and group (F = 32.97; p < 0.001). Heat pain threshold

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Fig. 2. The warm perception threshold and heat pain perception threshold for each studied subject and the average of warm perception threshold (black vertical line) in patients and controls in the lower extremities. In heat pain perception threshold, p value according to paired sample test between the affected and less-affected leg or according to independent sample test between patients and controls.

Fig. 3. The warm perception threshold and the heat pain perception threshold for each studied subject and the average of heat pain perception threshold (black vertical line) in patients and controls in the upper extremities. p Value according to independent sample test between patients and controls.

N2

was significantly lower in the affected-leg than in the less-affected leg in patients (t = 5.61, p < 0.001), but there were no differences between legs of controls (t = 1.71, p = 0.1). It was also significantly lower in the affected leg of patients than in the sham-affected leg of controls (t = 9.06, p < 0.001) and the in less affected leg of patients than the sham less-affected leg of controls (t = 2.11, p = 0.043).

4.4.2. Upper extremity Data for forearm stimulation are summarized in Fig. 3. There were no significant differences in warm perception threshold between patients and controls for forearm stimuli (t = 1.01, p = 0.32). Warm perception threshold of the affected arm in two patients (33.85° and 33.75° for each) was in the 95% CI of controls (CI: 33.6°–34.5°). Heat pain threshold was significantly lower in the less-affected arm of patients than in the arm of controls (t = 2.16, p = 0.04) (Fig. 3). In the 2 patients with arm involvement, heat pain perception threshold in the affected arm (37.8° and 37.18° for each) was outside of 95% CI of controls (CI: 42.53°–44.43°).

P2

A

50µV 100ms

B Stimulus

Fig. 4. Recordings of contact heat evoked potentials from patient with pPM. Fourteen traces are superimposed in the above figure and below figure shows average of those traces in each graph. The whole recording time was 1000 ms. (A) In the affected leg; (B) in the less-affected leg.

4.5. Evoked potentials Fig. 4 shows representative recordings of contact heat evoked potentials (CHEPS) from a patient with pPM in the affected and less-affected legs and Fig. 5 shows a summary of the mean data.

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Contact heat evoked potentials lower extremity 70

Amplitude of N2P2 (microV)

p=0.004 60 50 40 30 20 10 0

0

1

2

affected

3

4

less-affected

5

sham affected

patients

6

sham less-affected

controls

Fig. 5. The amplitude of N2/P2 for each studied subject and the average of evoked pain perception (black vertical line) of the affected leg and less-affected leg of all patients with pPM and of the legs of controls. CHEPS = contact heat evoked potentials. p Value according to paired sample test between the affected and the less-affected leg in patients.

p = 0.56). It was also not different between the legs of patients with respect to the legs of controls (p > 0.5 for each comparison).

No statistically significant differences were found in the latency of N2 (F = 0.90; p = 0.35) without interaction between side and group (F = 0.00; p = 0.99), neither in the latency of P2 (F = 0.41; p = 0.52) without interaction between side and group (F = 0.001; p = 0.97). However the amplitude of N2/P2 was significantly different (F = 7.53; p = 0.01) without interaction between side and group (F = 3.46; p = 0.07). The amplitude was significantly larger in the affected leg than in the less-affected leg in patients (32.9 ± 16.5 lV vs. 25.7 ± 13.0 lV respectively; t = 3.41, p = 0.004), but not between legs of controls (28.3 ± 16.3 lV vs. 26.89 ± 14.6 lV; t = 0.6,

4.6. Evoked heat pain Fig. 6 and Table 3 shows a summary of the data on evoked heat pain. There was a significant difference (F = 4.13; p = 0.05) and there was interaction between side and group (F = 13.44; p = 0.001). It was higher in the affected leg than in the less-affected leg in patients (t = 3.30, p = 0.005), but not between legs of controls

Evoked heat pain perception lower extremity p< 0.001

10

Numerical rating scale (0-10)

p=0.005

p=0.015

8

6

4

2

0

0

affected 1

less-affected 2

patients

3

sham affected 4

sham less-affected 5

6

controls

Fig. 6. The evoked heat pain perception for each studied subject and the average of evoked pain perception (black vertical line) of the affected leg and less-affected leg of all patients with pPM and of the legs of controls. p Value according to paired sample test between the affected and less affected leg or according to independent sample test between patients and controls.

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(p = 0.13). NRS was significantly higher in the affected leg of patients than in the sham-affected leg of controls (t = 5.25, p < 0.001) and in the less affected leg of patients than in the sham less-affected leg of controls (t = 2.60, p = 0.015). 4.7. In 2 patients without long-lasting and ongoing pain In the two patients who did not have long lasting or ongoing pain (Table 1), heat pain perception thresholds were lower in the affected leg than in the less affected leg (36.3° vs. 39.6° in one and 39.0° vs. 42.7° in the other) (95% CI: in controls 42.1–43.5°). One of two patients had also significant arm involvement from pPM and heat pain perception threshold was also lower in the affected arm than in the less-affected arm (37.8° vs. 41.5°)(95% CI of controls: 42.53°–44.43°). The two patients had evoked pain scores showing higher NRS in the affected leg than in the less affected leg (4.4 vs. 3.0 in one and 6.6 vs. 6.3 in the other) (95% CI in controls: 2.77–4.22). 4.8. Correlation analysis There was no significant correlation between ongoing pain intensity and evoked pain perception in the affected-leg (r = 0.22; p = 0.2), nor in the less-affected leg (r = 0.38; p = 0.08).

5. Discussion The main findings of our study are that pPM patients have: (1) significantly lower mechanical and heat pain perception threshold (more marked in the affected leg than in the less affected leg) in comparison to the controls, (2) significantly higher evoked pain score (more marked in the affected leg than in the less affected leg) in comparison to the controls, and (3) significantly larger amplitude of CHEPs in the affected leg than in the less affected leg. We have also found that patients with pPM complain often on musculoskeletal (nociceptive) pain that predominates in limbs contralateral to the affected one. Ongoing pain was reported by 13 out of the 15 patients studied (86.7%). Therefore, we have to conclude that ongoing pain is frequent in pPM patients. However, our patients reported ongoing pain (nociceptive ‘‘mainly musculoskeletal’’ pain) predominantly in the less affected leg, whereas our tests revealed the presence of hyperalgesia to nociceptive stimuli in the affected leg. A number of studies consider that ongoing pain in pPM patients may be highly dependent on psycho-social factors (Hirsh et al., 2010). However, it is also possible that it is due to overuse or abnormal compensatory activity in the limbs where the muscles are less wasted. While several explanations are possible for the musculoskeletal pain in pPM patients, there is little knowledge on the causes of evoked pain. According to published data, poliovirus is a neurotropic human enteroviruses and its disseminated infection in monkeys was characterized by severe panencephalitis involving both the pyramidal and extrapyramidal systems (Nagata et al., 2004). In humans, postmortem studies have shown a large diversity of lesions that compromise deep brain areas such as the reticular formation and basal ganglia (Bodian, 1949, 1947). Symptoms such as cold intolerance, cognitive difficulties, sleep disturbances, dysphagia, and sensory deficits have been described in pPM patients, suggesting dysfunction in neural networks beyond the motor system (Araujo et al., 2010; Soderholm et al., 2010; Terre-Boliart and Portell-Soldevila, 2010; Prokhorenko et al., 2008; Hazendonk and Crowe, 2000). Hyperalgesia might be another manifestation of central nervous system dysfunction.

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Another possible cause of evoked hyperalgesia in these patients is the impairment of the descending inhibitory pain control system, as a likely part of the cortico-spinal tract. Poliovirus spreads along nerve pathways, preferentially replicating in and destroying motor neurons within the spinal cord inducing flaccid paralysis in one or more limbs (MMWR Recomm Rep., 1997). It has been reported that activation of the cerebral cortex, particularly of the sensori-motor area, results in powerful excitatory and inhibitory actions on interneurons in the spinal cord. This is probably one of the mechanisms by which cortical stimulation carries inhibitory influences over ascending inputs (Garcia-Larrea et al., 1999; Andersen et al., 1962). Lindblom and Ottosson (1957) reported that stimulation of corticospinal fibers can inhibit dorsal horn neurons. On the other side, it has been demonstrated that electrical stimulation of motor axons in the posterior limb of the internal capsule or chronic motor cortex stimulation suppressed severe spontaneous pain associated with central nervous system lesions (Tsubokawa et al., 1991; Adam and Hosobuchi, 1974). There is reorganization of the motor cortex in patients with poliomyelitis, even if this is not correlated with motor performance or symptoms of post-polio syndrome (Oliveri et al., 1999; Lupu et al., 2008). The authors concluded that a rearrangement in human motor pathways targeting muscles affected by a lower motor neuron lesion occurs in pPM (Oliveri et al., 1999). MEPs were depressed after fatiguing exercise and there was a tendency to slower recovery of muscle performance (Lupu et al., 2008). These changes occurring after polio may allow the motor cortex to activate a greater proportion of the motor neurons innervating affected muscles (Lupu et al., 2008). Therefore, we may speculate that the destruction of motor neurons by pPM might cause dysfunction at various levels of the corticospinal motor tract (spinal cord, brainstem or motor cortex), which in turn facilitates hyperalgesia in PM patients. CHEPs amplitude in pPM patients was larger in the affected leg than in the less affected leg. The anterior cingulate cortex (ACC) is one potential site for the effect to take place since the N2-P2 components are generated mainly in the ACC (Lenz et al., 1998; Inui et al., 2003). Anatomic studies have shown dense neural connections between M1 and ACC (Dum and Strick, 1991; Morecraft and Van Hoesen, 1992). Possible explanations for CHEPs amplitude enhancement are sensitization of primary afferent pathways, a defect in descending nociceptive inhibitory control, or higher attention toward the affected limb from pPM (Garcia-Larrea et al., 2002; Treede et al., 2003). Our study has several limitations. (1) We recorded the nociceptive evoked potentials in our controls and patients using contact heat stimuli and only from Cz. Whether recording from other points in the scalp or using other types of nociceptive stimulation, such as laser or electrical stimulation, could have given rise to abnormalities is, therefore, unknown. (2) We based our analysis of CHEPs in the relatively small number of traces (only 14 traces for each subject). However, we believe that our main results are not influenced by these limitations. (3) We have not recorded eye movements and, even though subjects were warned not to blink during the study, some unadverted blinks could have induced artefacts in CHEPs. However, this limitation applies to all subjects and, obviously, to the CHEPs elicited from both lower limbs in patients. In conclusion, pPM-related hyperalgesia suggests a dysfunction of the nociceptive pathway that might be due to sensitization of primary afferent pathways and/or dysfunction in the descending inhibitory pain control system. However, we cannot exclude possible implication of higher attention toward the affected limb from pPM. Hyperalgesia in pPM should be taken into account in the routine clinical evaluation and management of these patients.

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